PT  - JOURNAL ARTICLE
AU  - Zhiye Tang
AU  - Chia-en A. Chang
TI  - Energy Barriers, Molecular Motions, and Residence Time in Ligand Dissociation: A Computational Study on Type II Inhibitors Binding to CDK8/CycC
AID  - 10.1101/169607
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 169607
4099  - http://biorxiv.org/content/early/2017/07/28/169607.short
4100  - http://biorxiv.org/content/early/2017/07/28/169607.full
AB  - It is important but unclear how protein-ligand system motions affect free energy profiles, create energy barriers, and lead to slow residence time. We computed residence time (RT) and potential of mean force (PMF) of the dissociations of five structure-kinetic relationship (SKRs) series inhibitors of CDK8/CycC using metadynamics and milestoning theory. By using a novel way to represent the reaction coordinate based on principal component analysis (PCA), we found one-to-one mapping of hydrogen bond (H-bond) breakage and protein domain motions with the energy barriers in the PMFs. This work provides a novel and well-defined approach to study the dissociation kinetics of large and flexible systems.RTresidence timePMFpotential of mean forceSRKstructure-kinetic relationshipPCAprincipal component analysisH-bondhydrogen bondMDMolecular dynamicsCVcollective variable